tbuckley/cabot-search huggingface dataset:
Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients
Authors: Solène Marie, Kayla L. Frost, Raymond K. Hau, Lucy Martinez-Guerrero, Jailyn M. Izu, Cassandra M. Myers, Stephen H. Wright, Nathan J. Cherrington
Journal: Acta Pharmaceutica Sinica B (2022)

The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters. Non-alcoholic steatohepatitis (NASH) causes disease-specific alterations to the absorption, distribution, metabolism, and excretion (ADME) processes, including a decrease in protein expression of basolateral uptake transporters, an increase in efflux transporters, and modifications to enzyme activity. This can result in increased drug exposure and adverse drug reactions (ADRs). Our goal was to predict drugs that pose increased risks for ADRs in NASH patients. Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease, mainly non-alcoholic fatty liver disease (NAFLD), 54 of which are known substrates of transporters and/or metabolizing enzymes. Since NASH is the progressive form of NAFLD but is most frequently undiagnosed, we identified other drugs at risk based on NASH-specific alterations to ADME processes. Here, we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH, based on their transport and/or metabolism processes. It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients, especially when eliminated through multiple pathways altered by the disease. Therefore, these results may inform clinicians regarding the selection of drugs for use in NASH patients.
The Dual ErbB1/ErbB2 Inhibitor, Lapatinib (GW572016), Cooperates with Tamoxifen to Inhibit Both Cell Proliferation- and Estrogen-Dependent Gene Expression in Antiestrogen-Resistant Breast Cancer
Authors: Isabel Chu, Kimberly Blackwell, Susie Chen, Joyce Slingerland
Journal: Cancer Research (2005)

Abstract Effective treatment of estrogen receptor (ER)-positive breast cancers with tamoxifen is often curtailed by the development of drug resistance. Antiestrogen-resistant breast cancers often show increased expression of the epidermal growth factor receptor family members, ErbB1 and ErbB2. Tamoxifen activates the cyclin-dependent kinase inhibitor, p27 to mediate G1 arrest. ErbB2 or ErbB1 overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction in p27 levels and inhibition of its function. Here we show that the dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), can restore tamoxifen sensitivity in ER-positive, tamoxifen-resistant breast cancer models. Treatment of MCF-7pr, T-47D, and ZR-75 cells with lapatinib or tamoxifen alone caused an incomplete cell cycle arrest. Treatment with both drugs led to a more rapid and profound cell cycle arrest in all three lines. Mitogen-activated protein kinase and protein kinase B were inhibited by lapatinib. The two drugs together caused a greater reduction of cyclin D1 and a greater p27 increase and cyclin E-cdk2 inhibition than observed with either drug alone. In addition to inhibiting mitogenic signaling and cell cycle progression, lapatinib inhibited estrogen-stimulated ER transcriptional activity and cooperated with tamoxifen to further reduce ER-dependent transcription. Lapatinib in combination with tamoxifen effectively inhibited the growth of tamoxifen-resistant ErbB2 overexpressing MCF-7 mammary tumor xenografts. These data provide strong preclinical data to support clinical trials of ErbB1/ErbB2 inhibitors in combination with tamoxifen in the treatment of human breast cancer.
Safety and efficacy of jaktinib in the treatment of Janus kinase <scp>inhibitor‐naïve</scp> patients with myelofibrosis: Results of a phase <scp>II</scp> trial
Authors: Yi Zhang, Hu Zhou, Zhongxing Jiang, Dengshu Wu, Junling Zhuang, Wei Li, Qian Jiang, Xiuli Wang, Jinwen Huang, Huanling Zhu, Linhua Yang, Xin Du, Fei Li, Ruixiang Xia, Feng Zhang, Jianda Hu, Yan Li, Yu Hu, Jing Liu, Chenghao Jin, Kai Sun, Zeping Zhou, Liqing Wu, Wenjuan Yu, Jie Jin
Journal: American Journal of Hematology (2022)

Myelofibrosis (MF) is associated with several constitutional symptoms. Currently, there are few therapeutic options for MF. Jaktinib, a novel, small-molecule inhibitor of JAK, is currently being studied for its potential to treat MF. This phase 2 trial investigated efficacy and safety of jaktinib in the treatment of MF patients. The primary end point was the proportion of patients with ≥35% reduction in spleen volume (SVR35, proportion of patients with ≥35% reduction in spleen volume) at week 24. The secondary end points included improvement of anemia, rates of symptom response, and safety profile. Between January 8, 2019 and August 29, 2020, 118 patients were recruited and treated with either jaktinib 100 mg BID or 200 mg QD. At week 24, 54.8% (34/62) of patients in the 100 mg BID group and 31.3% (15/48) in the 200 mg QD group achieved SVR35 (p = .0199). Jaktinib treatment increased hemoglobin level to ≥20 g/L in 35.6% (21/59) of patients with hemoglobin ≤100 g/L at baseline. The proportion of patients who achieved a ≥50% improvement in total symptom score at week 24 was 69.6% (39/56) in the BID group and 57.5% (23/40) in the QD group. The most common ≥ grade 3 hematological treatment-emergent adverse events (TEAEs; ≥ 10%) were anemia (100 mg BID: 24.2%, 200 mg QD: 28.8%), thrombocytopenia (16.7%, 11.5%), and neutropenia (3.0%, 11.5%). All non-hematological TEAEs were mild. These results indicate that jaktinib can shrink the spleen, improve anemia, and other clinical symptoms with good tolerability.
EAU Guidelines on Prostate Cancer. Part II: Treatment of Advanced, Relapsing, and Castration-Resistant Prostate Cancer
Authors: Nicolas Mottet, Joaquim Bellmunt, Michel Bolla, Steven Joniau, Malcolm Mason, Vsevolod Matveev, Hans-Peter Schmid, Theo Van der Kwast, Thomas Wiegel, Filiberto Zattoni, Axel Heidenreich
Journal: European Urology (2011)
ANTONIO EGAS MONIZ (1874-1955) PORTUGUESE NEUROLOGIST
Journal: JAMA (1968)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A roadmap for clinical trial design in marginal zone lymphoma
Authors: Juan Pablo Alderuccio, Thomas Habermann, Russ Kuker, Craig H. Moskowitz, Andrew D. Zelenetz, Izidore S. Lossos
Journal: American Journal of Hematology (2022)

Marginal zone lymphoma (MZL) is commonly underrepresented in clinical trials collectively studying mostly nodal indolent lymphomas.In this manuscript we propose new inclusion and response criteria defined by MZL subtype and disease location for those with extranodal MZL. Progression of disease within 24 months is associated with poor outcomes in MZL and future studies should assess the efficacy of novel agents in this population.
Surveillance Stress Testing “POST-PCI” — A Future Class III Recommendation?
Authors: Jacqueline E. Tamis-Holland
Journal: New England Journal of Medicine (2022)

More than 100 years ago, Einthoven reported the presence of ST-segment changes on electrocardiography in a patient during exercise.1 His discovery led to the development of the modern-day stress test. In patients with known coronary artery disease, the stress test is useful in assessing residual ischemia after an acute myocardial infarction or in cases of incomplete revascularization or when treating symptomatic patients who have had previous revascularization. It is also commonly used to guide exercise therapies before cardiac rehabilitation. Less is known regarding the role of routine surveillance stress testing in asymptomatic patients after percutaneous coronary intervention (PCI). The 2021 . . .
Anticoagulation in Atrial Fibrillation and Rheumatic Heart Disease
Authors: Gregory Y H Lip
Journal: New England Journal of Medicine (2022)

The landscape for stroke prevention in atrial fibrillation has been changed by the availability of the direct oral anticoagulants (DOACs) that have been tested in large, prospective, randomized trials for stroke prevention in patients with so-called nonvalvular atrial fibrillation. However, the definition of what is valvular or nonvalvular atrial fibrillation has been subject to much debate. The general consensus is that patients with atrial fibrillation and clinically significant valvular heart disease (defined as the use of prosthetic mechanical heart valves or moderate-to-severe mitral stenosis) should be treated with vitamin K antagonists (e.g., warfarin), whereas all other patients with atrial fibrillation . . .
Rivaroxaban in Rheumatic Heart Disease–Associated Atrial Fibrillation
Authors: Stuart J. Connolly, Ganesan Karthikeyan, Mpiko Ntsekhe, Abraham Haileamlak, Ahmed El Sayed, Alaa El Ghamrawy, Albertino Damasceno, Alvaro Avezum, Antonio M.L. Dans, Bernard Gitura, Dayi Hu, Emmanuel R. Kamanzi, Fathi Maklady, Golden Fana, J. Antonio Gonzalez-Hermosillo, John Musuku, Khawar Kazmi, Liesl Zühlke, Lillian Gondwe, Changsheng Ma, Maria Paniagua, Okechukwu S. Ogah, Onkabetse J. Molefe-Baikai, Peter Lwabi, Pilly Chillo, Sanjib K. Sharma, Tantchou T.J. Cabral, Wadea M. Tarhuni, Alexander Benz, Martin van Eikels, Amy Krol, Divya Pattath, Kumar Balasubramanian, Sumathy Rangarajan, Chinthanie Ramasundarahettige, Bongani Mayosi, Salim Yusuf
Journal: New England Journal of Medicine (2022)

Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).
Routine Functional Testing or Standard Care in High-Risk Patients after PCI
Authors: Duk-Woo Park, Do-Yoon Kang, Jung-Min Ahn, Sung-Cheol Yun, Yong-Hoon Yoon, Seung-Ho Hur, Cheol Hyun Lee, Won-Jang Kim, Se Hun Kang, Chul Soo Park, Bong-Ki Lee, Jung-Won Suh, Jung Han Yoon, Jae Woong Choi, Kee-Sik Kim, Si Wan Choi, Su Nam Lee, Seung-Jung Park
Journal: New England Journal of Medicine (2022)

There are limited data from randomized trials to guide a specific follow-up surveillance approach after myocardial revascularization. Whether a follow-up strategy that includes routine functional testing improves clinical outcomes among high-risk patients who have undergone percutaneous coronary intervention (PCI) is uncertain.
Microsurgical Treatment of Transient Cerebral Ischemia
Authors: Duke S. Samson
Journal: JAMA (1979)

Extracranial-intracranial arterial bypass is a microneurosurgical procedure recently introduced in the treatment of a variety of cerebrovascular ischemic states. Fifty patients with transient ischemic attacks (TIAs) localized to the distribution of the internal carotid artery underwent this procedure during a 48-month period. All have been followed up for at least 14 months after surgery. There were no operative deaths, and notable postoperative morbidity has been experienced in less than 8% of cases. Seventy-six percent of patients have been asymptomatic since surgery, 14% have continued to experience TIAs, and 6% have had completed strokes (2% occurring in the operative hemisphere). (<i>JAMA</i>241:376-378, 1979)
Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies
Authors: Milad Nazarzadeh, Zeinab Bidel, Hamid Mohseni, Dexter Canoy, Ana-Catarina Pinho-Gomes, Abdelaali Hassaine, Abbas Dehghan, David-Alexandre Tregouet, Nicholas L Smith, Kazem Rahimi
Journal: Cardiovascular Research (2022)

Abstract Aims Evidence for the effect of elevated blood pressure (BP) on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic BP and the risk of VTE. Methods and results Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.93, 95% confidence interval (CI): (0.92–0.94)]. Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic BP and VTE, both in the one-sample [odds ratio (OR): 0.69, (95% CI: 0.57–0.83)] and two-sample analyses [OR: 0.80, 95% CI: (0.70–0.92)]. Conclusion We found an increased risk of VTE with lower BP, and this association was independently confirmed in two Mendelian randomization analyses. The benefits of BP reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further BP reduction should be made cautiously.
The Goulstonian Lectures ON SPINAL INJURIES OF WARFARE: Delivered before the Royal College of Physicians of London
Authors: G. Holmes
Journal: BMJ (1915)

DURING-; the past tlhirteenu months we hiave been able to observe seivral lhtunidred cases of spinal injury, and at present hlave clinical notes on over 300; these wvill form the basis of the remarks anad conclusions whichll will be put for%vard in the naext two lectures.
Chemoimmunotherapy for Meningeal Melanocytoma of the Thoracic Spinal Cord
Authors: Dharmvir S. Verma
Journal: JAMA (1979)

THE MEDIAN survival of patients with primary melanomas of the CNS is approximately five months. A pigmented primary lesion of leptomeninges, usually causing symptoms from local expansion, has also been described and variously called pigmented meningioma, melanotic meningioma, and meningeal melanocytoma.<sup>1-5</sup>Thorough excision may result in cure or at least ensure a prolonged survival.<sup>3</sup> The occasional spontaneous disappearance or regression of the primary lesion in malignant melanoma and studies suggesting involvement of the immune system in host defenses have led to various immunotherapeutic approaches in the control of this and other kinds of neoplasms. We know of no previous description in the literature of treatment of meningeal melanocytoma other than surgical removal of the local tumor. This case of meningeal melanocytoma emphasizes its rare occurrence and recurring clinical course if not excised completely. <h3>Report of a Case</h3> A 71-year-old woman was admitted to the neurosurgery service in August
Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease
Authors: Michelle L. O’Donoghue, Robert P. Giugliano, Stephen D. Wiviott, Dan Atar, Anthony Keech, Julia F. Kuder, KyungAh Im, Sabina A. Murphy, Jose H. Flores-Arredondo, J. Antonio G. López, Mary Elliott-Davey, Bei Wang, Maria Laura Monsalvo, Siddique Abbasi, Marc S. Sabatine
Journal: Circulation (2022)

Background: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking. Methods: The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE [FOURIER Open-Label Extension]) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected. Results: A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C &lt;40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75–0.96]; P =0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68–0.93]; P =0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60–0.99]; P =0.04). Conclusions: Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for &gt;8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02867813 and NCT03080935.
CAR T Cells Contend with Myeloma in the Bone Marrow Microenvironment
Authors: Charlotte E. Graham, Marcela V. Maus
Journal: Blood Cancer Discovery (2022)

Summary: In this issue of Blood Cancer Discovery, Dhodapkar and colleagues find that myeloid, dendritic, and endogenous T-cell populations in the bone marrow microenvironment are associated with progression-free survival (PFS) in multiple myeloma patients responding to B-cell maturation antigen–targeted CAR T cells. Immunosuppressive myeloid cells are associated with short PFS, but a diverse T-cell receptor repertoire and more dendritic cells are associated with a longer PFS, suggesting a potential role for epitope spreading. See related article by Dhodapkar et al., p. 490 (6).
Air Pollution and Coronary Vasomotor Disorders in Patients With Myocardial Ischemia and Unobstructed Coronary Arteries
Authors: Massimiliano Camilli, Michele Russo, Riccardo Rinaldi, Andrea Caffè, Giulia La Vecchia, Alice Bonanni, Giulia Iannaccone, Mattia Basile, Rocco Vergallo, Cristina Aurigemma, Carlo Trani, Giampaolo Niccoli, Filippo Crea, Rocco A. Montone
Journal: Journal of the American College of Cardiology (2022)